In a conventional manufacturing process, preparing a solution of a shear sensitive material from an initial slurry that requires filtration to remove unwanted impurities offers various disadvantages. For example, agitation of the starting slurry in the process vessel can create decreased particle size which can then clog the pores of the filter unit. In addition, filtering the slurry using a traditional filtration system where the product feed stream flows through the pores of the filter can produce a low permeate flow rate and clogged pores.
In the conventional manufacturing process, the layout of the equipment is variable, but typically some of the equipment required to produce a large batch of a solution of a shear sensitive material is permanently installed in the process facility. The filter unit may be located below the slurry vessel so that gravity can aid in draining the contents onto the filter. All of the equipment used in the conventional manufacturing process requires the appropriate ancillary support functions in addition to water, electricity, and pressurized gas. In addition, cleaning all of the individual units requires manual intervention. In fact, each of the batch operations used in the conventional manufacturing process requires manual input and/or manual transfer.
For example, in the conventional manufacturing process, an aqueous solution of N1-(3,4-dichlorobenzyl)-N5-octyl-biguanide gluconate concentrate is typically produced by performing multiple individual operations as a series of manual batch processes. FIG. 1 shows the steps of the conventional manufacturing process, comprising a desalting process and a solubilization process.
In the desalting process, sodium hydroxide is added to a vessel containing an aqueous slurry of N1-(3,4-dichlorobenzyl)-N5-octyl-biguanide hydrogen chloride salt to generate the free base, also as a slurry. This free base slurry is then transferred to a filtration unit where the sodium hydroxide and liberated chloride are removed in the filtrate. To insure adequate removal, the process of resuspending the resulting free base cake in water and refiltering is repeated multiple times. The washed wet free base cake is then harvested.
In the solubilization process, the free base is added to a clean vessel containing an aqueous solution of the surfactant, poloxamer (Pluronic™). This is performed by manually scooping the wet cake into the reactor vessel via an appropriate opening (manway, etc.) or by first suspending the free base in water as a slurry and pulling it into the reactor under vacuum or motivated by a pump. Gluconic acid (glucono-δ-lactone solution) is then added, causing the slurry to dissolve to form a transparent solution. After a volume adjustment, samples are withdrawn for pH measurement and the pH is adjusted manually by adding the appropriate amount of acid or base. Thereafter, samples are pulled for quantification and a calculated amount of water is added to the solution to achieve the targeted N1-(3,4-dichlorobenzyl)-N5-octyl-biguanide gluconate concentration. After the solution is passed through a 0.45 μm clarification filter, it is ready for testing and further processing into product.
For a large scale process, however, an automated process in a self-contained process unit offers advantages over the conventional manufacturing process. These advantages can include portability, automation, a fully contained system that requires minimal handling and minimizes manual human intervention, controlled chemical introduction, and an automated mechanism for cleaning the self-contained process unit without disassembly of the unit.
Many of the advantages of the automated self-contained process result from the recirculating nature of the process. The self-contained process unit allows for a circulating stream of materials within the unit. In addition, the circulating nature permits other chemicals required of the process to be introduced via one or more pumps into the circulating process stream.
Moreover, a circulating process stream permits the continuous filtration of the desired product using a tangential flow filtration system through at least one filter. To maintain an adequately high permeate flow rate through the tangential flow filters, filters can be added in series. As compared to using a single filter, it was anticipated that placing two filters in series would result in a permeate flow rate of less than double and that placing three filters in series would result in a permeate flow rate of less than triple. Surprisingly, it was discovered that the permeate flow rates were more than double for two filters in series and more than triple for three filters in series.
In addition, a tangential flow filtration system where the particles (retentate) flow over the filter and the liquid (permeate) passes through the hollow membranes of the filter unit allows a back-flush flow of clean liquid through the filter to dislodge particles and to replace the volume of liquid lost as the permeate stream. Accordingly, the present invention is directed to addressing one or more of the needs described above.